Non-conventional GluN3A signaling modulates memory ontogeny, formation and consolidation

During early brain development, an excess production of synapses occurs, resulting in the establishment of weak functional connections between neurons. Subsequently, neuronal activity refines the initial circuitry by strengthening and maintaining specific connections while suppressing (pruning) others. This process ultimately leads to the formation of more precise and long-lasting connections. Compelling evidence suggests that even subtle imbalances in synapse maturation and pruning can contribute to various severe brain disorders, including autism, schizophrenia, bipolar disorder, and neurodegenerative conditions that manifest in adulthood. GluN3A subunit-containing NMDA receptors (GluN3A-NMDARs) have emerged as crucial regulators of this synaptic refinement. GluN3A-NMDARs are typically expressed before and during critical periods of postnatal development. They play a role in preventing premature synapse maturation and stabilization until sensory experience occurs, subsequently targeting less utilized or non-active synapses for pruning. Previous research from our lab have revealed that GluN3A-NMDARs exhibit selective inhibition of a specific subset of activity- and NMDAR-regulated signaling pathways. Among these pathways, the mTOR pathway, particularly the multiprotein complex mTORC1, stands out due to its crucial involvement in stimulating dendritic protein synthesis in response to synaptic signals. Building on this work, here we investigated whether GluN3A-NMDARs impact cognition-related behaviors and the mechanisms through which they exert their effects. We found that GluN3A bi-directionally affects mice performance in contextual and associative learning tasks: deleting GluN3A enhances mice performance while increasing its expression impairs mice ability to form associative memories. To expand our investigation, we utilized genetic tools to further elucidate the role of GluN3A in memory processes. Through these tools, we were able to demonstrate that GluN3A exerts its influence on memory by being expressed in excitatory neurons. Importantly, we discovered that the impact of GluN3A on memory is not limited to critical periods of development but continues to be significant throughout adulthood. We also discovered that GluN3A limits cognitive behaviors by constraining mTORC1-signaling and that its deletion enhances long-term potentiation (LTP) in vivo. To further our understanding, we studied postnatal and aged mice with ablated GluN3A expression. We found that removing GluN3A-NMDARs increased protein synthesis and accelerated the ontogeny of memories, limiting the temporal window of infantile amnesia and that GluN3A ablation protects against age-related memory loss. The findings presented in this thesis significantly contribute to our comprehension of the mechanisms through which GluN3A-NMDARs, impact the brain and influence behaviors essential for our interaction with the environment. These results pave the way for novel avenues of research aimed at enhancing our understanding of NMDARs function. Moreover, our experiments provide compelling evidence supporting the therapeutic prospects of targeting GluN3A-NMDARs as a means to develop memory-enhancing treatments

Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly

De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here, we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mechanistic target of rapamycin (mTOR) kinase, and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancement

Taller de Neurociencias

This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/.Láminas para Taller de Neurociencias impartido para profesores no universitarios en la Semana de la Ciencia de la Asociación Ars Creatio. Este taller también se ha impartido para alumnos de varios colegios de Torrevieja y para el público en general, impartidos en el Museo de Historia Natural de Torrevieja

Grey matter changes on brain MRI in subjective cognitive decline: a systematic review

Abstract Introduction People with subjective cognitive decline (SCD) report cognitive deterioration. However, their performance in neuropsychological evaluation falls within the normal range. The present study aims to analyse whether structural magnetic resonance imaging (MRI) reveals grey matter changes in the SCD population compared with healthy normal controls (HC). Methods Parallel systematic searches in PubMed and Web of Science databases were conducted, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Quality assessment was completed using the Newcastle-Ottawa Scale (NOS). Results Fifty-one MRI studies were included. Thirty-five studies used a region of interest (ROI) analysis, 15 used a voxel-based morphometry (VBM) analysis and 10 studies used a cortical thickness (CTh) analysis. Ten studies combined both, VBM or CTh analysis with ROI analysis. Conclusions Medial temporal structures, like the hippocampus or the entorhinal cortex (EC), seemed to present grey matter reduction in SCD compared with HC, but the samples and results are heterogeneous. Larger sample sizes could help to better determine if these grey matter changes are consistent in SCD subjects